Method and apparatus for electrostatically depositing a medicament powder upon predefined regions of a substrate

ABSTRACT

Apparatus and a concomitant method for electrostatically depositing select doses of medicament powder at select locations on a substrate. Specifically, the apparatus contains a charged particle emitter for generating charged particles that charge a predefined region of a substrate and a charge accumulation control circuit for computing the amount of charge accumulated upon the substrate and deactivating the emitter when a selected quantity of charge has accumulated. Additionally, a triboelectric charging apparatus charges the medicament powder and forms a charged medicament cloud proximate the charged region of the substrate. The medicament particles within the medicament cloud electrostatically adhere to the charged region. The quantity of charge accumulated on the substrate at the predefined region and the charge-to-mass ratio of the medicament powder in the cloud control the amount (dose) of medicament deposited and retained by the substrate. Consequently, this apparatus accurately controls both medicament dosage and deposition location. Furthermore, since the substrate can be of any dielectric material that retains an electrostatic charge, the apparatus can be used to deposit medicament on substrates that are presently used in oral medicament consumption, e.g., substrates that are used to fabricate suppositories, inhalants, tablets, capsules and the like.

[0001] The invention relates to dry powder deposition techniques andmore particularly, the invention relates to a technique forelectrostatically depositing a dry powder medicament in accurate,repeatable doses upon a dielectric substrate.

BACKGROUND OF THE DISCLOSURE

[0002] Powdered medication is typically administered orally to a personas a tablet or capsule, or as an inhalant. The prior art discloses anumber of techniques for administering doses of inhalable dry powders tothe lungs of a patient. Generally, inhalers are mechanical systems thatgenerate a metered cloud of medicament powder for inhalation by apatient. Many of these prior art inhaler devices use chlorofluorocarbon(CFC) gas to facilitate generating a metered cloud of medicament forinhalation. However, since CFCs are no longer used in consumer products,other techniques for generating the medicament cloud have been explored.

[0003] One example of a non-CFC, prior art inhaler is disclosed in U.S.Pat. No. 4,811,731 issued Mar. 14, 1989 (the “'731 patent”). This patentdiscloses an inhaler that contains a plurality of measured doses ofmedicament stored in a blisterpack. Upon use, one of the blisters in theblisterpack is punctured and a patient inhales the medicament from thepunctured blister via a mouthpiece of the inhaler. In the '731 patent,the medicament dosage is measured and deposited in each blister of theblisterpack using conventional, mechanical measuring and depositingtechniques. Detrimentally, such mechanical deposition techniques do notapply repeatable doses of medication into each blister of theblisterpack. Typically, some of the medicament adheres to the mechanicaldeposition system and, as such, reduces the amount of medicationdeposited into a given blister. The degree of adhesion depends upon theenvironment in which the deposition is conducted, e.g., the ambienthumidity, temperature and the like. Since a mechanical depositionprocess is used to apply medicament to other orally administrableplatforms, the same dose variation evident in inhaler doses occurs forother platforms as well. As such, a more accurate technique is needed inthe art for depositing medication into any orally administrable platformincluding inhalers, tablets, capsules, suppositories, and the like.

[0004] An example of a technique for producing orally administeredmedication tablet or capsule form is disclosed in U.S. Pat. No.4,197,289 issued Apr. 8, 1980. This technique utilizes an electrostaticdeposition process for depositing a medicament upon an edible substratethat is referred to in the '289 patent as a “web”. Using a conventionalcorona charging technique, this process continuously charges the web asthe web moves past the charging element. Thereafter, the web passesthough a compartment containing a medicament cloud. The medicament inthe cloud is attracted to the charged web and becomes depositedthereupon, i.e., the web becomes “loaded”. A spectroscopic monitoringsystem determines the amount of medication that has been deposited onthe web and generates a control signal that regulates the amount ofmedicament within the cloud chamber. As such, the '289 depositiontechnique uses an active feedback system to regulate the depositionprocess. To complete the process, the loaded web is cut into individualunits that can be combined with one another to define a medicament dose,e.g., a particular number of individual web units defines a single doseof the medication. The combined units are then encapsulated to formindividual, orally administrable doses of medication.

[0005] A disadvantage of the '289 technique is the requirement for anactive feedback system to control the deposition process. Such systemsare typically complex and require an integrated medicament measuringsystem to generate the control signals, e.g., such as the spectroscopicmonitoring system of the '289 patent. In using a feedback system, the'289 technique attempts to uniformly deposit the medicament across theentire web. Dosage control is therefore accomplished not by changing thedeposition quantity upon the web, but rather by combining a number ofweb units to form a dose. As such, the dosage control process is undulycomplicated. For example, to generate a uniform deposit of medicament,the electrostatic charge on the web must be uniform, the rate at whichthe web passes the charging element and the cloud compartment must beconstant, and the feedback system must accurately measure the amount ofdrug on the web and accurately control the amount of medication in thecloud compartment. Thereafter, assuming the medication was uniformlydeposited on the web, the web must be accurately cut into units that canbe combined and encapsulated to form doses of the medication. Each ofthe encapsulated doses is supposed to contain the same amount ofmedication as all other doses. However, such a complicated process isprone to error.

[0006] Therefore, a need exists in the art for a medicament depositionprocess that electrostatically deposits specific quantities of drypowder medication at particular locations on a dielectric substrate.Additionally, a need exists in the art for a technique for quantifyingan amount of electrostatic charge accumulated on the substrate and touse the quantified charge value to regulate the quantity of medicamentdeposited on the substrate.

SUMMARY OF THE INVENTION

[0007] The disadvantages heretofore associated with the prior art areovercome by an inventive technique for electrostatically depositing drypowdered medication at specific locations upon a dielectric substrate.Specifically, a conventional ionographic print head is utilized tocharge a particular region of a substrate. The substrate is a planar,dielectric layer positioned upon a conductive plate. To form adielectric layer that is in contact with the conductive plate, thedielectric layer may be deposited upon the plate, the dielectric layermay be in contact with but independent from the plate, or the plate maybe metallic plating deposited upon a lower surface of the dielectriclayer.

[0008] In operation, a potential is applied between the plate and theprint head such that the plate attracts ions generated by the printhead. Consequently, the ions electrostatically charge a region of thedielectric layer that lies between the plate and the print head.Selectively positioning the print head relative to the substrate selectsparticular regions of the substrate upon which to “print” the charge.The amount of charge accumulated at any one location depends upon thedwell time of the print head over that particular location and the ioncurrent between the print head and the plate.

[0009] Once a charge is accumulated on the substrate, a triboelectriccharging process produces a charged cloud of medicament proximate thecharged region of the substrate. The triboelectric charging processmixes, in a glass container, the dry powder medicament with a pluralityof glass or plastic beads. The mixing action charges the medicament. Agas is then used to blow the charged medicament from the container andinto a cloud proximate the charged surface of the substrate. Themedicament particles are typically oppositely charged with respect tothe charge on the substrate. As such, the medicament deposits itselfupon the charged region of the substrate. The deposition pattern of themedicament matches a charge pattern “printed” by the print head and theamount of medicament that adheres to the patterned region isproportional to the amount of charge accumulated by the substrate.Consequently, using the invention, the medicament can be accuratelypositioned on a substrate and the dose can be accurately controlled bycontrolling the amount of charge accumulated on the substrate.

[0010] In one embodiment of the invention, the print head is combinedwith charge measuring apparatus for quantifying the charge accumulatedon the substrate. The measuring apparatus measures the DC current (ioncurrent) between the print head and the conductive plate. Specifically,the plate is connected to an integrator that charges a capacitor as theions bombard the substrate. A comparator compares the integrator outputsignal to a threshold level. The threshold level represents a specificamount of charge to be accumulated on the substrate. When the integratoroutput signal exceeds the threshold level, the comparator deactivates anAC signal source that generates the ions within the print head. As such,the print head stops generating ions and charge no longer accumulates onthe substrate. Consequently, a specific amount of charge has beenapplied to the substrate and, when the medicament cloud is applied tothe charged surface, a particular amount of medicament adheres to thesubstrate. In this manner, the charge control process very accuratelycontrols the quantity of medicament that is retained by the substrate.

[0011] In a further embodiment of the invention, a reverse developmentprocess is used to electrostatically deposit medicament powder on asubstrate. In a reverse development process, a charge is deposited overthe entire substrate surface, except in regions where the medicament isto be deposited. To pattern the charge and generate uncharged regions,either the print head is selectively modulated (activated anddeactivated) as it is moved over the surface of the substrate or aphotoconductive substrate is used such that, after charging, light isused to selectively remove charge from particular regions of thesubstrate. In either instance, if, for example, a negative charge isapplied to the substrate, a negative charge is also applied to themedicament. As such, the medicament adheres to the substrate in theuncharged regions only, i.e., an electrostatic force is produced betweenthe conductive plate and the medicament in the uncharged regions.

[0012] The types of substrates upon which the medicament can bedeposited vary widely depending upon the ultimate application of themedication. For example, in an inhaler application, the substrate can bea flat, ceramic disk upon which a plurality of medicament doses arepositioned. A user may selectively remove and inhale each dose of themedicament from the disk using a venturi effect inhaler device.Alternatively, the disk may be a fabricated of a woven or perforateddielectric material. In this case, a user can directly position adelivery tube within the inhaler device over a selected dose ofmedicament stored on the disk. The user then inhales air through thedelivery tube and the air flow releases the medicament from thedielectric. The released medicament continues through the delivery tubeinto the user's lungs.

[0013] In a further example of the invention being used to producepharmaceutical substrates, including capsules, tablets, vaginal andrectal suppositories and the like, the electrostatic depositiontechnique of the invention is used to electrostatically deposit specificquantities of powdered medicament upon an edible or otherwisebiodegradable substrate. The substrate is then encapsulated in an inertmaterial to form a capsule, tablet, or suppository. Substrates usefulfor this application are typically polymeric substances that preferablyself-destruct or degrade in body fluids and/or enzymes. However, thesubstrate can be an indestructible substance that is readily eliminatedfrom the body once the medicament has been released from the substrateinto the body. Additionally, for example, the deposition technique ofthe invention can be used to deposit directly onto a pharmaceuticalsubstrate including an inhaler substrate, a capsule, tablet orsuppository. Thus, the present invention further provides a method ofmanufacturing a pharmaceutical substrate with medicament powderdeposited thereon, comprising electrostatically depositing themedicament powder on the substrate. Preferably, the electrostaticdeposition of the medicament occurs on a predefined region of thepharmaceutical substrate, such as the surface of a tablet inside theedges so that the edges of the tablet may be sealed.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The teachings of the present invention can be readily understoodby considering the following detailed description in conjunction withthe accompanying drawings, in which:

[0015]FIG. 1 depicts a cross-sectional view of an ionographic print headand a dielectric substrate supported by a conductive plate;

[0016]FIG. 2 depicts a schematic drawing of a charge accumulationcontrol circuit for use in conjunction with the print head of FIG. 1;

[0017]FIG. 3 depicts a cross-sectional view of a triboelectric chargingcontainer for charging a medicament powder and a cross-sectional view ofa portion of a substrate upon which the charged medicament powder isdeposited;

[0018]FIG. 4 depicts a flow chart of the electrostatic depositionprocess;

[0019]FIG. 5 depicts a top, perspective view of a substrate that hasbeen charged using a reverse development charging technique;

[0020]FIG. 6 depicts a cross-sectional view of the substrate along line6-6 in FIG. 5; and

[0021]FIG. 7 depicts a perspective view of an illustrative substratehaving had dry powder deposited at a plurality of select locationsthereupon and an illustrative inhalation device for releasing themedicament from the substrate.

[0022]FIG. 8 is a graphical representation of the charge density ofelectrostatically printed dots in nanoCoulombs on the x-axis versus theleft-hand y-axis which shows the diameter of the dots in mils, with thedata points shown as open squares; and the right-hand y-axis which showsthe weight of the dots in micrograms, with the data points shown asclosed squares.

[0023] FIGS. 9A-C are optical micrographs of depositions of a medicamentupon a 2 cm² polypropylene substrate using ion printing. FIG. 9A showsdots having a diameter of about 75 mil; FIG. 9B shows dots having adiameter of about 45 mils, and FIG. 9C shows dots having a diameter ofabout 37 mils.

[0024] To facilitate understanding, identical reference numerals havebeen used, where possible, to designate identical elements that arecommon to the figures.

DETAILED DESCRIPTION

[0025] The present invention is apparatus and a concomitant method forelectrostatically depositing a specific quantity of dry powdermedicament at select locations on a substrate. The apparatus contains anionographic print head, an AC signal supply for generating ions withinthe print head, a DC signal source for propelling the ions toward asubstrate, and a charge accumulation control circuit for computing theamount of charge accumulated upon the substrate and deactivating the ACsignal source when a specific quantity of charge has accumulated.Additionally, a triboelectric charging apparatus is used to charge themedicament powder and form a charged medicament cloud proximate apredefined region of the substrate that is charged by the print head.The medicament particles within the medicament cloud electrostaticallyadhere to the predefined region. The quantity of charge accumulated onthe substrate at the predefined region and the charge-to-mass ratio ofthe medicament powder in the cloud controls the amount (dose) ofmedicament that is deposited upon and retained by the substrate.Consequently, this apparatus accurately controls both medicament dosageand deposition location. Furthermore, since the substrate can befabricated of any dielectric material that will retain an electrostaticcharge, the apparatus can be used to deposit medicament on manysubstrates that are presently used in medicament consumption, e.g.,substrate materials used to fabricate suppositories, inhalants, tablets,capsules and the like.

[0026] Thus, according to the present invention, specific quantities ofpowdered medicament can be deposited onto a substrate. The substrate canthen be encapsulated, for example, to form a tablet. In addition toencapsulation, a pharmaceutical substrate having an electrostaticallydeposited powder thereon can also be formed by electrostatic depositiononto the pharmaceutical substrate itself provided that thepharmaceutical substrate can retain a corona charge for deposition ofthe medicament. In certain preferred embodiments, the pharmaceuticalsubstrate is an inhaler substrate, a tablet, capsule or suppository. Atablet, for example, can be tested to determine whether it can retain acorona charge as follows. The conductivity of a tablet can be determinedby measuring the DC impedance, by placing the tablet in an electricalcircuit between a voltage source and a picoammeter. The capacitance ofthe tablet can be measured by placing the tablet sample in parallel witha Hewlett Packard 4192A Low Frequency Impedance Analyzer set for 1 kHz.The tablets are preferably painted on both sides with a thin layer ofconductive silver paint to ensure good electrical contact.

[0027] If the tablet, as formulated, cannot retain a corona charge, thetablet is preferably coated, for example, with a surface coating thatretains a corona charge on the surface of the tablet. For example, anedible polymer can be used for the surface coating, such as natural orchemically modified starches and dextrins including lactose; otherpolysaccharides such as pectin, acacia, xanthin gum, guar gum and algin;phospholipids such as lecithin; proteins such as gelatin; cellulosederivatives such as sodium carboxymethylcellulose,hydroxyoropylmethylcellulose and hydroxyethylcellulose; syntheticpolymers such as polyvinylpyrrolidone and polyvinyl alcohol; or otheredible polymers, and preferably those which are hydrophobic. See alsoU.S. Pat. No. 4,197,289, which is incorporated by reference herein inits entirety.

[0028] Once the medicament is deposited on the tablet, the medicament ispreferably sealed onto the tablet by coating the tablets In certainembodiments, the tablet has an indentation for deposition of medicament,the indentation preferably being filled when the desired amount ofmedicament is deposited. The tablet is preferably sealed afterdeposition.

[0029] Thus, the present invention further provides a method ofmanufacturing a pharmaceutical substrate with medicament powderdeposited thereon, comprising electrostatically depositing themedicament powder on the substrate. In certain preferred embodiments,the pharmaceutical substrate is, for example, an inhaler substrate, atablet, capsule or suppository. Preferably, the electrostatic depositionof the medicament occurs on a predefined region of the substrate, suchas the surface of a tablet inside the edges so that the edges of thetablet may be sealed.

[0030]FIG. 1 depicts apparatus for depositing a predefined quantity ofcharge at a particular location on a dielectric substrate 110.Specifically, the apparatus 100 is comprised of an ion emitter commonlyreferred to as an ionographic print head 102, AC and DC signal sources104 and 106 for the print head, a charge control circuit 108 and adielectric layer 110 (substrate) supported by a conductive plate 112.More specifically, the print head 102 contains a first electrode 114separated from a second electrode 116 by an insulator 118. The AC signalsource 104 typically supplies a 5 MHz RF signal of approximately 1500peak-to-peak volts across the first and second electrodes. The secondelectrode contains an aperture that forms an ion generation region 120.The AC signal causes an electric field between the electrodes to form aplasma in region 120. Specifically, the air within this region becomesionized forming the plasma. To remove the ions 121 from the region andpropel them towards the substrate, a screen grid 122 is positioned in aspaced-apart parallel relation to the second electrode 116 and the grid122 contains an aperture 126 that is coaxially aligned with the region120. Insulating layer 124, located between the screen grid 122 and thesecond electrode 116, maintains the screen grid 122 in this spaced-apartrelation with respect to the second electrode 116.

[0031] Typically, to control ion extraction from region 120, a DCvoltage source 128 is connected between the screen grid and the secondelectrode. However, empirical study indicates that a voltage of zerovolts applied between the second electrode and the screen grid permitseffective extraction of ions from region 120. As such, the secondelectrode can be electrically connected to the screen grid as indicatedby dashed line 130. However, the optimum screen grid to second electrodevoltage may vary depending upon the screen grid bias voltage, the ACvoltage and frequency, and the particular structure of the ion emitter.Thus, for best results, a variable DC voltage source 128 should be usedto optimize ion extraction.

[0032] A bias voltage from a DC signal source 106 is applied to theconductive plate 112 and the screen grid 122. The source 106 supplies abias voltage of approximately 1200 volts that propels the ions throughthe screen grid aperture 126 toward the substrate 110. Additionally,acceptable charge deposition has resulted from bias voltages in therange of 400 to 600 volts. The ions form a path that generally followsthe electric field lines of force spanning between the screen grid andthe plate. The gap between the grid and the substrate is approximately20 mils. Also, the screen grid, by having this bias voltage appliedthereto, selects the polarity of ion that is propelled to the substrate,e.g., a negative biased screen grid propels positive ions toward thesubstrate, while a positive bias propels negative ions toward thesubstrate. Typically, the screen gridis negatively biased and theconductive plate is maintained at a ground (0 volt) potential. In thismanner, the screen grid assists in the propulsion of the negative ionsto negatively charge the substrate at a location on the substrate thatis directly below the print head.

[0033] The ion current that flows from the screen grid 122 to theplate-112, during any given unit of time, and returns through DC source106 is equal to the amount of charge accumulated on the substrate. Assuch, to measure the charge accumulation and control the amount ofcharge accumulated on the substrate, a charge control circuit 108 isconnected in series with the DC signal source. The charge controlcircuit (which is discussed in detail below with respect to FIG. 2)measures the current flowing between the plate 112 and the screen grid122. When the current attains a predefined level, the charge controlcircuit deactivates the AC signal source and, consequently, halts theflow of ions to the substrate. In essence, the charge control circuitmodulates the AC signal from the AC signal source. Upon cessation of theion flow, no further charge accumulation occurs on the surface of thesubstrate. Thus, the substrate attains and maintains a predefined chargequantity at a particular location on the substrate.

[0034] In the foregoing discussion, the print head was discussed asbeing an ion emitter having two electrodes and a screen grid. Suchemitters are commercially available as model 1013527 manufactured byDelphax, Inc. located in Toronto, Canada. It should be understood thatthis particular emitter arrangement is meant to be illustrative and thatother electrode and grid arrangements are available in the art thatwould produce the necessary localized charge accumulation on the surfaceof the substrate. Furthermore, the emitter can also be an electron beamemitter that propels a stream of electrons toward the substrate tolocally charge the surface of the substrate. As such, the inventiondescribed herein encompasses all possible forms of charged particleemitter that can conceivably charge the surface of a dielectricsubstrate in a localized manner.

[0035] Although an “off-the-shelf” ion emitter will sufficiently chargethe substrate, empirical study indicates that superior charge depositionis achieved when using a smaller screen grid aperture 126 than isgenerally available in an off-the-shelf emitter. As such, to reduce thesize of the charge accumulation area when using the model 1013527Delphax emitter, the standard emitter is fitted with a conductive plate(a retrofit screen grid) that reduces the typical 6 mil diameter screengrid aperture to a 1-2 mil diameter aperture. In other words, theretrofit screen grid having a 1-2 mil diameter aperture is coaxiallyaligned with the standard screen grid aperture to form a compositescreen grid with a 1-2 mil diameter aperture. The screen grid biasvoltage is applied to the retrofit screen grid. Of course, rather thanusing a retrofit screen grid, the emitter could merely be fabricatedwith a 1-2 mil screen grid aperture.

[0036]FIG. 2 depicts a schematic diagram of the charge control circuit108. The circuit contains a low pass filter (LPF) 200, an integrator202, a comparator 204 and a threshold level source 212. The integratorfurther contains a capacitor 206, a capacitor discharge component suchas a mechanical, electromechanical, or solid state switch 208, and ahigh impedance amplifier 210. Specifically, an input port of the filter200 is connected to the conductive plate 112 that supports thedielectric substrate 110. The filter removes any RF energy (e.g., ACsignal from the AC signal source) that is coupled from the emitter 102to the plate 112, leaving only the DC signal that represents the ioncurrent. The output port of the filter is coupled to the capacitor 206.The capacitor is connected between the output port and ground. As such,the capacitor charges to a voltage that represents the magnitude of theDC signal produced by the filter 200. The capacitor discharge component208 is connected across the capacitor for intermittently discharging thesignal accumulated in the capacitor. The discharge is typicallyaccomplished between depositions of medicament to remove the residualcharge from a previous deposit. The high impedance amplifier 210 isconnected to the capacitor and output port of the filter such that thesignal accumulated on the capacitor is amplified to a useful level.

[0037] The output of the integrator 202, the integrated signal, isapplied to one port of the comparator 204. The magnitude of theintegrated signal is directly proportional to the amount of chargeaccumulated upon the dielectric substrate 110, e.g., as the chargeaccumulates more ion current flows and the magnitude of the integratedsignal increases. A second port of the comparator is connected to athreshold voltage source 212. The source 212 provides a threshold signalto which the comparator compares the integrated signal. When theintegrated signal exceeds the threshold level, the charge controlcircuit 108 deactivates the AC signal source driving the print head.Conversely, as long as the integrated signal magnitude is less than thethreshold level, the AC signal source remains activated and the chargeaccumulates upon the substrate.

[0038] The charge accumulation on the substrate is proportional to thesize of the region that is charged by the print head. In accordance withionographic printing terminology, this region, which is typicallycircular, is commonly referred to as a “dot size”. The dot size isrelated to the accumulated charge by the following equation:$\begin{matrix}{{{dot}\quad {size}} = {\left( {{dot}\quad {size}_{0}} \right)\quad \left( \sqrt{\frac{q}{q_{o}}} \right)}} & (1)\end{matrix}$

[0039] where:

[0040] dot size is a diameter of a circular region in which charge isaccumulated on the substrate;

[0041] q is the accumulated charge quantity to produce a particular dotsize; and

[0042] q₀ is a reference charge quantity to generate reference dot size(dot size₀).

[0043] The reference charge quantity and dot size are empiricallypredetermined for a particular dielectric material and dielectricmaterial thickness. Once the reference charge quantity and reference dotsize are determined, equation (1) is used to compute the dot size forany given charge quantity. Thus, the threshold level in the chargecontrol circuit is correlated to one or more dot sizes. As such, thethreshold level is set to deactivate the AC signal source when aparticular level is exceeded such that a particular dot size isgenerated for that threshold level. Further, a series of selectablethreshold levels can be provided such that a user can select aparticular dot size to be generated for a particular medicament beingdeposited at that time. Thus, this form of medicament deposition is veryflexible and very useful in controlling the medicament dose that isdeposited upon the substrate.

[0044] Once the substrate is charged, the medicament must then bedeposited upon the charged region of the substrate. In this regard, amedicament cloud is provided proximate the charged region of thesubstrate. The medicament particles in the cloud, being positivelycharged (if the substrate is negatively charged), are attracted to thenegatively charged region of the substrate and electrostatically depositthemselves on the charged region of the substrate. Of course, themedicament cloud is negatively charged if the substrate has beenpositively charged.

[0045]FIG. 3 depicts a cross-sectional view of apparatus 300 forcharging the medicament particles and depositing the charged particlesupon the substrate. Specifically, the invention uses a triboelectriccharging technique to charge the medicament. Such a techniqueeffectively charges the medicament particles such that, when dispersedinto a cloud, the charge-to-mass ratio on each particle is substantiallyuniform throughout the cloud. Consequently, given a repeatable quantityof charge on the substrate and such a repeatable charge-to-mass ratio onthe medicament particles, a repeatable amount of medicament is attractedto and remains electrostatically adhered to the substrate. Theelectrostatic attraction or adhesion between the medicament powder andthe substrate remains, without significant degradation, for months.

[0046] Medicament charging and deposition apparatus 300 contains atriboelectric charger 302, medicament powder 304, and the chargedsubstrate 110 supported upon a conductive plate 112. The substrate has acharged region 310 (dot size) that has been locally charged aspreviously discussed with an ion or electron emitter. The triboelectriccharger 302 is a cylindrical, glass container 306 containing a pluralityof glass or plastic beads 308 (e.g., four beads) and the powderedmedicament 304. Illustratively, the beads have a diameter of between 50and 200 microns and are fabricated of one of the following materialsTeflon, kynar, polypropylene, maroon polypropylene, fluoro-treatedglass, glass, amino-treated glass, polystyrene, white miliken and thelike. The container 306 has a mesh, typically wire, at each end. Themesh defines openings (e.g., 400 mesh screen) that permit the medicamentpowder to ingress and egress from the container. In use, the medicamentis added to the container, the mesh ends of the container are closed offand the beads and medicament mixture is shaken for 1 to 10 minutes.During the shaking process, a charge accumulates on the particles of thepowder. Once charged, a gas (e.g., air or nitrogen) is blown through thecontainer and medicament particles form a cloud proximate the surface ofthe substrate.

[0047] The amount and polarity of the charge on the medicament particlesdepends upon the fabrication material of the beads. By measuring thecharge-to-mass ratio of the powder using a faraday cage, the inventorshave found that by selecting a particular bead material the chargecharacteristics are controllable. For example, charging a mometasonefuroate (MF) powder in a glass container using four beads having 50 to100 micron diameters at 70 degrees Fahrenheit and 45% relative humidity,resulted in the charge-to-mass ratios for various bead materials shownin Table 1. TABLE 1 Bead Material Charge Polarity Ratio (μC/gm) Teflonpositive 35 Kynar positive 30 Polypropylene positive 6.5 Maroonpolypropylene positive 10 Fluoro-treated glass positive 17.8 Glassnegative 6.5 Amino-treated glass negative 39.8 Polystyrene negative 42.7White miliken negative 7.7

[0048] By appropriate selection of the bead material, the charge-to-massratio can be varied form 6.5 to 43 μC/gm and the charge is eitherpositive or negative. When accurately depositing a medicament, a lowmicrogram quantity of medicament (e.g., 20-40 μg) requires a relativelyhigh charge-to-mass ratio and a high microgram quantity of medicament(e.g., 20-40 μg) requires a relatively low charge-to-mass ratio. Usingthe triboelectric medicament charging technique in combination with theelectrostatic substrate charging technique, a 10 to 200 μg quantity ofmedicament can be accurately positioned on the substrate. Furthermore,the adherence of such quantities of medicament to a 2 mil thick,polypropylene substrate is strong enough to withstand a 48 inch droptest without dislodging any of the medicament from the substrate. Thissubstantial adhesion property is attributed to electrostatic and shortrange van der Waals forces.

[0049] Once deposited, the substrate is positioned near a vacuum systemto remove any medicament powder that has not electrostatically adheredto the substrate. In a practical medicament dosing substrate, aplurality of locations on the substrate are charged and then medicamentis deposited at each of the charged locations. Thereafter, the vacuumsystem removes any excess medicament powder that is not adhered to thecharged locations.

[0050] Alternatively, since the unadhered medicament powder (backgroundpowder) is typically a relatively small quantity of medicament, it cansimply be left on the substrate. If this approach is used, the amount ofcharge deposited should be slightly reduced such that slightly lessmedicament is adhered to the substrate.

[0051]FIG. 4 depicts a flow chart summarizing the process used toelectrostatically deposit medicament onto a substrate. Depositionprocess 400 begins, at step 402, by positioning the print head over aparticular location on a substrate. At step 404, a user selects the dotsize to be “printed” by selecting a threshold level for the chargecontrol circuit. The process, at step 406, activates the print head andbegins bombarding the selected location on the substrate with ions. Theprocess queries, at step 408, whether the threshold level has beenexceeded by the accumulated charge on the substrate. If the query isnegatively answered, the print head remains active and charge continuesto accumulate on the substrate. When the query of step 408 isaffirmatively answered, the process, at step 410, deactivates the printhead. At this point in the process a “dot” of charge having a diametercommensurate with the dot size selected in step 404 has been depositedat the selected location upon the substrate. Of course, rather than asingle dot, the print head could be moved relative to the substrate toform a charged pattern on the substrate, e.g., a line, a square, acircle, and the like.

[0052] Once the charge is deposited, the triboelectric chargingapparatus produces a charged cloud of medicament proximate the surfaceof the substrate. Specifically, the process, at step 412, produces thiscloud of medicament as described above with respect to FIG. 3. Apredefined dose of medicament adheres to the charged dot on thesubstrate. As discussed above, the quantity of medicament in the dosedepends on the charge accumulated on the substrate and thecharge-to-mass ratio of charge on the medicament powder. At step 414,excess medicament is removed, for example, by a vacuum system. Theexcess medicament can be recycled for deposition at another time.Lastly, at step 416, the substrate and its medicament are packaged.

[0053] The foregoing electrostatic deposition process can further beused in what is known as a reverse development process. In general, thereverse development process scans the print head over the substrate (orthe substrate can be moved past the print head) to deposit charge at alllocations on the substrate except those locations where the medicamentis to be deposited.

[0054]FIG. 5 depicts a top view of a disk-shaped substrate 500 having aplurality of medicament deposition locations 502. The gray area on thesubstrate indicates the area in which a charge is deposited by the printhead. Conversely, locations 502 contain no charge.

[0055] As depicted in the cross-sectional view of a portion of thesubstrate 502 in FIG. 6 taken along line 6-6 in FIG. 5, if the substratecharge is negative, the conductive plate 112, positioned beneath thesubstrate 500, is positively charged across its entire surface thatcontacts the substrate 500. The medicament 504 is negatively chargedusing, for example, the triboelectric charging technique discussedabove. The negatively charged medicament electrostatically adheres tothe substrate 500 in uncharged region 502, i.e., the negatively chargedmedicament is attracted to the positively charged plate. Additionally,the negatively charged medicament is repelled from the negativelycharged surface of the substrate. Consequently, medicament onlyaccumulates and adheres to the uncharged substrate regions 502. Torelease the medicament, the plate is discharged, typically by grounding.Such discharge removes the electrostatic force maintaining themedicament upon the substrate. Consequently, once the charge is removed,the medicament can be easily removed from the substrate using a venturior direct inhalation device (as discussed below with respect to FIG. 7).To facilitate release of single medicament doses, the conductive plateis segmented (or patterned) and each plate segment is located below eachregion 502. As such, each plate segment can be individually charged anddischarged. Thus, each dose of medicament can be individually releasedfrom the substrate.

[0056] A variation of the reverse deposition technique forms anotherembodiment of the invention. This alternative involves utilization of aphotoconductive disk as a substrate upon which the medicament isdeposited. Illustratively, the photoconductive disk is a polymericsubstrate coated with a photoconductive zinc oxide in a resin binder. Aprint head charging technique is used to negatively charge the entiresurface of the disk. Thereafter, a light mask having a plurality ofapertures therethrough is positioned over the substrate and the mask isbathed in light. Consequently, the substrate surface exposed to thelight via the apertures in the mask is discharged of the negativecharge. After the mask is removed, the disk is charged in a manner thatresembles the substrate depicted in FIG. 5, i.e., charge is deposited inall locations except locations where the medicament is to be deposited.The negatively charged medicament powder is deposited in the unchargedregions in the same manner as described above with respect to FIG. 6.The medicament powder is released from the substrate by exposing aselected dose of the medicament and an area surrounding the selecteddose to light. Such light exposure discharges the electrostatic forceand releases the medicament powder from the substrate. Thereafter, themedicament can be inhaled using a venturi or direct inhalation device asdiscussed below.

[0057]FIG. 7 depicts an illustrative substrate having medicamentdeposited at predefined locations using one of the electrostaticdeposition processes discussed above with respect to FIGS. 4, 5 and 6.The substrate 110 of FIG. 7 is a disk shaped dielectric that contains aplurality of locations 310 to which medicament 304 electrostaticallyadheres. A central hole 700 is provided to permit the substrate to besupported within an inhaler device 702. This exemplary inhaler device702 uses the venturi principle to extract the medicament from thesubstrate. The inhaler contains a housing (not shown) that surrounds thesubstrate and supports the venturi inhaler apparatus 704 and thesubstrate 110. The venturi inhaler apparatus contains a main air flowtube 710 having a mouthpiece 706 and an inlet end 708. Approximatelymid-way along the main air flow tube is a medicament tube 712 thatorthogonally intersects and is coupled to the main tube 710. Themedicament tube 712 is positioned over a medicament location 310 byrotating the substrate 110 relative to the venturi apparatus 704. Apatient then inhales through the mouthpiece 706 drawing air throughinlet end 708 of the tube 710. As air flows toward the mouthpiece 706,the venturi effect also draws air through tube 712. As air is drawnthrough tube 712, the medicament is dislodged from the substrate andcarried to the patient's mouth. When another dose is required, thepatient rotates the substrate to the next dose on the disk and againinhales the medicament.

[0058] To permit a substantial air flow along tube 712, the substrate,rather than being a solid layer of dielectric material, may be a wovenor perforated substrate. Such substrates include a metallic mesh coatedwith a dielectric material such as Teflon, a textile such as silk, aperforated solid dielectric layer, and the like. The perforations aresmall relative to the particle size of the medicament, but large enoughto allow air to pass therethrough. As such, when a patient inhales onthe mouthpiece, air passes through the substrate 110 and along tube 712.The air flow carries the medicament to the patient.

[0059] Additionally, when using a perforated substrate, a venturi effectinhaler is not necessary and can be substituted with a simple inhalationtube. Such an inhaler device contains a flexible inhalation tubesupported by a housing and having an inlet end located proximate amedicament location. In essence, this is the venturi inhalationapparatus without a main air flow tube 710, where the patient merelyinhales on the medicament tube 712. In use, an inlet end of aninhalation tube is positioned proximate a medicament location byrotating the substrate within the housing. Thereafter, the patientsimply inhales the medicament directly from the perforated substrate,through the inhalation tube and into their lungs. The perforatedsubstrate significantly increases the velocity of the air flow thatremoves the medicament from the substrate over that of a venturi effectdevice used in combination with a solid substrate.

[0060] Those skilled in the art will realize that many other forms ofinhaler devices can be employed to dislodge the medicament from thesubstrate, including those that employ compressed gas or air to removethe medicament and generate a inhalable cloud. Any of these inhalerdevices are to be considered within the scope of the invention.

[0061] In each of the foregoing embodiments of the invention, thesubstrate may be fabricated of Teflon, polystyrene, polypropylene andthe like. In general, any material that will retain an electrostaticcharge is sufficient. The substrate, may or may not be perforated toenable inhalation of air through the substrate as discussed above. In afurther example of the invention being used to produce oral medication,including capsules, tablets, vaginal and rectal suppositories and thelike, the electrostatic deposition technique of the invention is used toelectrostatically deposit specific quantities of powdered medicamentupon an edible substrate such as cellulose. The substrate is thenencapsulated in a inert material to form a capsule, tablet, orsuppository. Substrates useful for this application are typicallypolymeric substances that preferably self-destruct or are degraded inbody fluids and/or enzymes. However, the substrate can be anon-destructible substance that is readily eliminated from the body oncethe medicament has been released into the body from the substrate.

[0062] Although various embodiments which incorporate the teachings ofthe present invention have been shown and described in detail herein,those skilled in the art can readily devise many other variedembodiments that still incorporate these teachings.

[0063] The accuracy of deposition using methods and apparatus of theinvention is further illustrated by the following non-limiting example.

EXAMPLE 1 Accuracy of Deposition of Medicament onto Inhaler Substrate

[0064] The correlation between the amount of charge generated in thesubstrate and the amount of medicament deposited was determined bymeasuring the current applied, the time in which the current wasapplied, the total charge deposited, and the average maximum weight fora charge:mass ratio of 10 μC/g. The results are shown in Table 2 below.TABLE 2 ave. max. Total Dot weight for Time charge Diameter q/m = 10Current (nA) (seconds) (nC) (mils) μC/g 3.5 0.13 0.45 37 6.5 12 0.131.56 45 22 16.5 0.13 2.15 54 30 19.5 0.13 2.54 60 37 40 0.13 5.7 75 7340 0.13 17.1 99 140

[0065] The data in the foregoing table is depicted graphically in FIG.8, which proves a y-axis on the left side of the graph showing thediameter of the dots in mils, with the data points shown as opensquares; a y-axis on the right side of the graph showing the weight ofthe dots in micrograms, with the data points shown as closed squares;and an x-axis showing the charge density of the dots in nanoCoulombs.The data, as depicted in the graph in FIG. 8, shows that therelationship between the charge density of the dot and the diameter ofthe dot is substantially linear, and the relationship between the chargedensity of the dot and the weight of the dot are also substantiallylinear. Thus, the charge density can be used to accurately determine aprecise amount of medicament to be deposited upon the inhaler substrateusing the ion printing method. Using this methods, small dosages from 10μg to 100 μg of medicament were accurately deposited, within ±10%.

[0066] FIGS. 9A-C are optical micrographs of depositions of a medicamentupon a 2 cm² polypropylene substrate using ion printing. FIG. 9A showsdots having a diameter of about 75 mil; FIG. 9B shows dots having adiameter of about 45 mils, and FIG. 9C shows dots having a diameter ofabout 37 mils.

What is claimed is:
 1. Apparatus-for electrostatically depositing amedicament powder upon selected regions of a substrate, said apparatuscomprising: a charged particle emitter for generating charged particles;a substrate spaced apart from said emitter and located upon a conductiveplate, where said charged particles, upon impact with a predefinedregion of a surface of said substrate, locally charge said substrate atsaid predefined region; and a powder cloud forming means for generatinga cloud of medicament powder proximate said predefined region on saidsubstrate, where a plurality of powder particles within said cloud areelectrostatically adhered to said predefined region of said substrate.2. The apparatus of claim 1 wherein said substrate is perforated.
 3. Theapparatus of claim 1 wherein the substrate is a woven mesh coated with adielectric material.
 4. The apparatus of claim 1 wherein the substrateis a tablet.
 5. The apparatus of claim 1 further comprising: a chargecontrol means, coupled to said emitter and said conductive plate, forcomparing the charge accumulated upon the substrate to a thresholdcharge value and for deactivating said emitter when said comparisongenerates a deactivation signal.
 6. The apparatus of claim 5 whereinsaid charge control means further comprises an integrator forintegrating the charge accumulated upon said substrate and forgenerating a voltage value indicative of the accumulated charge on thesubstrate.
 7. The apparatus of claim 5 wherein said charge control meanscontrols a size of the charged region on the substrate by measuring theaccumulated charge on the substrate relative to a reference charge valuethat corresponds to a reference size of he charged region.
 8. Theapparatus of claim 6 wherein said charge control means further comprisesa low pass filter connected between said conductive plate and saidintegrator.
 9. The apparatus of claim 1 wherein said powder cloudforming means is a triboelectric charging apparatus.
 10. The apparatusof claim 9 wherein said triboelectric apparatus further comprises aplurality of beads that are fabricated of a selected material thatgenerates substantially the same charge-to-mass ratio for each particleof medicament powder within said charged cloud of medicament powder. 11.The apparatus of claim 1 wherein said medicament powder is deposited ata plurality of predefined regions upon said substrate.
 12. The apparatusof claim 1 further comprising means for releasing said medicament fromsaid substrate.
 13. The apparatus of claim 12 wherein said releasingmeans is a venturi effect inhaler.
 14. The apparatus of claim 12 whereinsaid releasing means is a inhalation tube for inhaling said medicamentdirectly from the substrate.
 15. The apparatus of claim 14 wherein saidsubstrate is perforated.
 16. The apparatus of claim 14 wherein thesubstrate is a woven mesh coated with a dielectric material. 17.Apparatus for electrostatically depositing a medicament powder uponselected regions of a substrate, said apparatus comprising: a chargedparticle emitter for generating charged particles; a substrate spacedapart from said emitter and located upon a conductive plate, where saidcharged particles, upon impact with a predefined region of a surface ofsaid substrate, locally charge said substrate at said predefined region;and a powder cloud forming means for generating a cloud of medicamentpowder proximate said predefined region on said substrate, where aplurality of powder particles within said cloud are electrostaticallyadhered to any region other than said predefined region of saidsubstrate.
 18. The apparatus of claim 17 wherein said substrate is atablet.
 19. The apparatus of claim 17 further comprising: a chargecontrol means, coupled to said emitter and said conductive plate, forcomparing the charge accumulated upon the substrate to a thresholdcharge value and for deactivating said emitter when said comparisongenerates a deactivation signal.
 20. The apparatus of claim 17 whereinsaid powder cloud forming means is a triboelectric charging apparatus.21. The apparatus of claim 20 wherein said triboelectric apparatusgenerates substantially the same charge-to mass ratio for each particleof medicament powder within said charged cloud of medicament powder. 22.The apparatus of claim 17 wherein said medicament powder is depositedupon said substrate at a plurality of regions other than said predefinedregion.
 23. The apparatus of claim 17 further comprising means forreleasing said medicament from said substrate.
 24. The apparatus ofclaim 23 wherein said releasing means is a venturi effect inhaler. 25.The apparatus of claim 24 wherein said releasing means is an inhalationtube for inhaling said medicament directly from the substrate.
 26. Theapparatus of claim 25 wherein said substrate is perforated.
 27. Theapparatus of claim 25 wherein the substrate is a woven mesh coated witha dielectric material.
 28. Apparatus for electrostatically depositing amedicament powder upon selected region of a substrate, said apparatuscomprising: a charged particle emitter for generating charged particles;a photoconductive substrate spaced apart from said emitter and locatedupon a conductive plate, where said charged particles, upon impact witha surface of said photoconductive substrate, charge the surface of saidsubstrate; a light mask, applied to said charged substrate surface, forselectively applying light to cause discharging of any region of saidphotoconductive substrate not covered by said light mask; and a powdercloud forming -means for generating a cloud of medicament powderproximate said predefined region on said substrate, where a plurality ofpowder particles within said cloud are electrostatically adhered to anyregion other than a charged region of said substrate.
 29. The apparatusof claim 28 wherein said substrate is a tablet.
 30. The apparatus ofclaim 28 wherein said powder cloud forming means is a triboelectriccharging apparatus.
 31. The apparatus of claim 30 wherein saidtriboelectric apparatus generates substantially the same charge-to-massratio for each particle of medicament powder within said charged cloudof medicament powder.
 32. The apparatus of claim 28 wherein saidmedicament powder is deposited upon said photoconductive substrate at aplurality of uncharged regions.
 33. The apparatus of claim 28 furthercomprising means for releasing said medicament from said substrate. 34.The apparatus of claim 33 wherein said releasing means is a venturieffect inhaler.
 35. The apparatus of claim 34 wherein said releasingmeans is an inhalation tube for inhaling said medicament directly fromthe substrate.
 36. The apparatus of claim 34 wherein said substrate isperforated.
 37. The apparatus of claim 34 wherein the substrate is awoven mesh coated with a dielectric material.
 38. A method ofelectrostatically depositing a medicament powder upon a selected regionof a substrate, said method comprising the steps of: positioning acharged particle emitter proximate a selected region of a substrate;activating said emitter to cause charged particles to propagate fromsaid emitter to said substrate, whereby said selected region of saidsubstrate becomes charged; deactivating said emitter when a particularquantity of charge has accumulated upon said substrate; and generating amedicament cloud proximate said selected region of said substrate, wheremedicament particles in said medicament cloud electrostatically adhereto said selected region of said substrate.
 39. The method of claim 38wherein said activating and deactivating steps further comprise the stepof controlling a signal source that drives the ion emitter.
 40. Themethod of claim 38 further comprising the steps of measuring a chargedparticle current flowing between said emitter and said substrate todetermine said particular quantity of charge.
 41. The method of claim 40wherein said measuring step further comprises the steps of integratingsaid charged particle current and comparing the integrated chargedparticle current value to a threshold value that is indicative of saidparticular quantity of charge.
 42. The method of claim 40 wherein saidmedicament charge generating step further comprises a step of activatinga triboelectric charging apparatus.
 43. The method of claim 42 whereinsaid triboelectric charging apparatus activating step generates asubstantially uniform charge-to-mass ratio within said cloud having acharge polarity that is opposite a charge polarity of the chargeaccumulated in said predefined region of said substrate.
 44. A method ofelectrostatically depositing a medicament powder upon a selected regionof a substrate, said method comprising the steps of: positioning acharged particle emitter proximate a substrate; activating said emitterto cause charged particles to propagate from said ion emitter to saidsubstrate, where said selected region of said substrate becomes chargedand a non-selected region remains uncharged; deactivating said emitterwhen a particular quantity of charge has accumulated upon saidsubstrate; and generating a medicament cloud proximate said non-selectedregion of said substrate, where medicament particles in said medicamentcloud electrostatically adhere to said non-selected region of saidsubstrate.
 45. The method of claim 44 wherein said activating anddeactivating steps further comprise the step of controlling a signalsource that drives the emitter.
 46. The method of claim 44 furthercomprising the steps of measuring a charged particle current flowingbetween said emitter and said substrate to determine said particularquantity of charge.
 47. The method of claim 46 wherein said measuringstep further comprises the steps of integrating said charged particlecurrent and comparing the integrated charged particle current value to athreshold value that is indicative of said particular quantity ofcharge.
 48. The method of claim 44 wherein said medicament chargegenerating step further comprises a step of activating a triboelectriccharging apparatus.
 49. The method of claim 48 wherein saidtriboelectric charging apparatus activating step generates asubstantially uniform charge-to-mass ratio within said cloud having acharge polarity that is identical to a charge polarity of the chargeaccumulated in said predefined region of said substrate.
 50. A method ofmanufacturing a pharmaceutical substrate with medicament powderdeposited thereon, comprising electrostatically depositing saidmedicament powder on the substrate.
 51. The method of claim 50 whereinthe electrostatic deposition of the medicament occurs on a predefinedregion of the substrate.
 52. The method of claim 50 wherein thesubstrate is selected from the group consisting of a tablet, capsule,suppository and an inhaler substrate.